SNARE (soluble N-ethylmaleimide-sensitive factor attachment protein receptor; SNAP receptor) proteins are a large protein superfamily consisting of 60 or more members in yeasts and mammalian cells, and the primary role of SNARE proteins is to mediate vesicle fusion. That is, SNARE proteins mediate the fusion of vesicles with their target membrane bound to compartments such as a lysosome. As a specific example, SNAREs mediate docking of synaptic vesicles with the presynaptic membrane in neurons.
Meanwhile, to regulate the relaxation and contraction of muscles, there is a neuromuscular junction in the upper layer of muscle, and synaptic vesicles are loaded in this nerve terminal. Muscles contract by receiving a message of a neurotransmitter transmitted from the inside of synaptic vesicles, and for the release of such a neurotransmitter, SNARE proteins form a complex, and this enables neurotransmitters to be docking with muscles. In particular, for the release of a neurotransmitter, a synaptic vesicle containing the neurotransmitter is required to be fused with a presynaptic membrane so that a passage between two boundaries can be formed, and at this time, a fundamental force for such membrane fusion is provided by SNARE complexes comprising three kinds of proteins. Particularly, a release passage of a neurotransmitter is opened by membrane fusion between a synaptic vesicle and a presynaptic membrane, and a t-SNARE complex, which is a complex of a syntaxin-1a protein and a SNAP-25 protein that are attached to a target membrane, and v-SNARE attached to a vesicle are involved in this pathway, and such SNARE proteins are twisted in a spiral shape.
In the membrane fusion, the rearrangement of a lipid bilayer, which is widely known in the art, occurs. Since biomembranes strongly repel against each other, the membranes cannot be spontaneously fused, and thus a strong external force is required to overcome the repulsive force between the membranes. At this time, SNARE proteins generate such a strong force enough to overcome the repulsive force between the membranes. That is, the formation of a SNARE complex is a source of the force to overcome intermembrane repulsive force and is a main action in extracellular exocytosis including the release of a neurotransmitter [Weber etc., Cell, 92, 759-772 (1998)].
As an example, pores of the skin are generally distributed in the facial skin but can be visually recognized particularly in nasal and buccal sites, and the appearance of pores varies from person to person according to intrinsic and extrinsic factors such as gender, genetic factors, aging, acnes, chronic UV exposure, and the like. The reason for the widening of the pores is that as sebum is excessively secreted or skin aging begins, collagen fibers and elastic fibers, which support pore walls, are denatured and decreased, resulting in loss of skin elasticity and skin laxity. Since the contraction or relaxation of muscles (arrector pili muscles) attached to hairs is under the control of the sympathetic and parasympathetic nerves, the pores may be reduced or enlarged by neural control. The sympathetic nerve is slightly distant from muscles and narrows pores, whereas the parasympathetic nerve is located near muscles and enlarges pores. When the parasympathetic nerve is selectively suppressed, a compensating action of the sympathetic nerve contracts muscles attached to hairs, thereby reducing pores.
On the other hand, if the conjugation and twisting of SNARE are not fully completed, membrane fusion fails, and, accordingly, the release of neurotransmitters does not occur, and this eventually results in no movement of muscles. This indicates that, through this process, the generation of wrinkles produced by frequently used muscles can be prevented and pre-formed wrinkles can also be alleviated. In addition, by inhibiting the release of neurotransmitters, hyperhidrosis, which refers to excessive sweating caused by the stimulation of sweat glands due to the release of a larger amount of neurotransmitters than required, may be alleviated.
In other words, due to the SNARE formation inhibitory effect, the generation of wrinkles caused by the movement of muscles may be inhibited and the formed wrinkles may be alleviated, and hyperhidrosis, which is one of the diseases caused by excessive release of neurotransmitters, may be treated, prevented, and alleviated.
Furthermore, in a case in which the formation of SNARE protein complexes specific to mast cells in vivo is inhibited, mast cell degranulation is inhibited, and allergic diseases and autoimmune diseases are thereby treated and prevented (Woska J. R. Jr. and Gillespie M. E., J. Cell Mol. Med., 2012, 16(4), 649-656).
Representative materials targeting the SNARE include bacterial neurotoxin which causes botulism food poisoning and tetanus, and the like. For example, a neurotoxin derived from Clostridium botulinum is a main ingredient of a drug known as “Botox,” which is known to be used mainly in cosmetic procedures such as wrinkle removal, or the like, and is used also to treat the secretion of many neurotransmitters and/or muscle-related diseases, such as strabismus, blepharospasm, vocal cord dysfunction, torticollis, cardiomyopathy, ulcer and gastric acid reflux disorders, appetite decrease, pancreatic diseases, stretchmarks, overactive bladder, anal fissure, poliomyelitis, muscular pain, hip deformities, hyperhidrosis, back pain, neck pain, chronic headache, cranial nerve disorder, and the like. Specifically, Botox is known to exhibit a therapeutic effect on the above-listed diseases because a neurotoxin, which is a main ingredient of Botox, inhibits complex formation by acting specifically on SNARE present in neurons, thus suppressing membrane fusion, resulting in blocking of the release of neurotransmitters, thereby inhibiting the movement of muscles or the sympathetic or parasympathetic nervous system. However, Botox components are toxic substances and thus may cause side effects; therefore, there is a need to be cautious in determining a dose or application site thereof.